ABSTRACT Cardiovascular disease (CVD) remains a significant concern in adults living with HIV (AHIV) on antiretroviral therapy (ART). Little is known about subclinical or early upstream CVD pathogenesis in youth living with perinatally acquired HIV (YPHIV) who stand to benefit the most from early identification of subclinical CVD. ART expansion has reduced pediatric HIV mortality, allowing YPHIV to reach adulthood, but not without lifelong exposure to immune activation, inflammation, and ART, all of which potentiate CVD. Several studies including ours have shown subclinical myocardial dysfunction in YPHIV, but few have evaluated underlying metabolic pathways or been conducted with well-matched comparison groups of youth living with non- perinatally acquired HIV (YNPHIV) and HIV-unexposed uninfected (HUU) youth in sub-Saharan Africa, where currently 90% of the world?s children with HIV reside. We have demonstrated high rates (25%) of right ventricular systolic dysfunction and insulin resistance (21%) in our cohort of South African YPHIV. In addition, our YPHIV have an increased risk for endothelial dysfunction and dyslipidemia compared to uninfected youth. However, detailed sensitive imaging data to comprehensively measure myocardial and vascular dysfunction are urgently needed in YPHIV to understand the role of these precursors in end conditions such as heart failure and CVD which we have shown to be more prevalent in AHIV. In addition, studies in YPHIV of underlying metabolic pathways involved in early/primordial factors across the cascade of myocardial/vascular dysfunction resulting in CVD are lacking and critical to providing insight into early prediction and potential mitigation of the development of cardiometabolic complications among YPHIV into adulthood. For this proposal we will leverage the Cape Town Adolescent and Antiretroviral Cohort (CTAAC) to assess whether ART-treated perinatally acquired HIV is associated with worsened subclinical myocardial or vascular dysfunction over time using YNPHIV and HUU youth comparison groups of similar age, sex, and body surface area (BSA) and employing cardiovascular magnetic resonance imaging (CMR), a sensitive multiparametric method of investigating multiple cardiovascular domains. Next, we will use novel metabolomics techniques to explore whether a signature cluster of intermediary or proinflammatory metabolites representing eicosanoid imbalances and mitochondrial shifts in fatty acid oxidation are different in YPHIV compared to YNPHIV or HUU youth and are associated with subclinical myocardial or vascular dysfunction in YPHIV. Lastly, we will explore how inflammation correlates with these eicosanoid imbalances and mitochondrial shifts in fatty acid oxidation in YPHIV. These results will expand our understanding of the pathogenesis and interplay between metabolic dysregulation and subclinical myocardial dysfunction as well as elucidate key pathways of cardiac dysfunction which may identify those YPHIV at highest risk for CVD, informing future potentially targetable interventions such as dietary measures to alter metabolic fuel utilization or possible immune-modulating therapy.